DNA adducts, mutant frequencies, and mutation spectra in various organs of lambda lacZ mice exposed to ethylating agents.
To investigate tissue-specific relations between DNA adducts and mutagenesis in vivo, lambda lacZ transgenic mice were treated i.p. with N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS). In liver, bone marrow, and brain DNA from mice sacrificed at several time points after treatment O6-ethylguanine (O6-EtG) and N7-ethylguanine (N7-EtG) levels were determined as well as the mutant frequency (MF) in lacZ. In liver DNA of ENU- and DEN-treated mice, the bulk of O6-EtG was removed at 3 days after treatment, while the MF continued to increase thereafter. This suggests that O6-EtG is not the major premutagenic lesion in the liver. Indeed, sequence analysis of mutants showed only 24% GC-->AT transitions, consistent with the O6-EtG lesion, and 28% TA-->AT transversions, expected from O2-ethylthymine. In bone marrow after ENU treatment, a maximum mutation induction occurred at 3 days post-treatment, of which 43% were GC-->AT mutations and 22% were TA-->AT mutations. This suggests that in bone marrow O6-EtG may be a major premutagenic lesion at the 3-day time point. In liver and bone marrow, EMS treatment gave rise to a high level of N7-EtG and a low level of O6-EtG but no increase in MF. No adducts or mutation induction were observed in bone marrow of DEN-treated mice. No MF increase was observed in the brain of either ENU- or EMS-treated mice, although O6- and N7-adducts were present.
Mientjes
E J
EJ
Department of Molecular Toxicology, TNO Nutrition and Food Research Institute, Zeist, The Netherlands.
Luiten-Schuite
A
A
van der Wolf
E
E
Borsboom
Y
Y
Bergmans
A
A
Berends
F
F
Lohman
P H
PH
Baan
R A
RA
van Delft
J H
JH
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts; D004052:Diethylnitrosamine / Q000633:toxicity*; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D007763:Lac Operon; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens / Q000633:toxicity*
D018736:DNA Adducts; D009153:Mutagens; C022007:7-ethylguanine; D004052:Diethylnitrosamine; C007673:6-ethylguanine; D006147:Guanine; D005020:Ethyl Methanesulfonate; D005038:Ethylnitrosourea